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Interactions between ?-catenin and transforming growth factor-? signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP).

ABSTRACT: Interactions between transforming growth factor-? (TGF-?) and Wnt are crucial to many biological processes, although specific targets, rationale for divergent outcomes (differentiation versus block of epithelial proliferation versus epithelial-mesenchymal transition (EMT)) and precise mechanisms in many cases remain unknown. We investigated ?-catenin-dependent and transforming growth factor-?1 (TGF-?1) interactions in pulmonary alveolar epithelial cells (AEC) in the context of EMT and pulmonary fibrosis. We previously demonstrated that ICG-001, a small molecule specific inhibitor of the ?-catenin/CBP (but not ?-catenin/p300) interaction, ameliorates and reverses pulmonary fibrosis and inhibits TGF-?1-mediated ?-smooth muscle actin (?-SMA) and collagen induction in AEC. We now demonstrate that TGF-?1 induces LEF/TCF TOPFLASH reporter activation and nuclear ?-catenin accumulation, while LiCl augments TGF-?-induced ?-SMA expression, further confirming co-operation between ?-catenin- and TGF-?-dependent signaling pathways. Inhibition and knockdown of Smad3, knockdown of ?-catenin and overexpression of ICAT abrogated effects of TGF-?1 on ?-SMA transcription/expression, indicating a requirement for ?-catenin in these Smad3-dependent effects. Following TGF-? treatment, co-immunoprecipitation demonstrated direct interaction between endogenous Smad3 and ?-catenin, while chromatin immunoprecipitation (ChIP)-re-ChIP identified spatial and temporal regulation of ?-SMA via complex formation among Smad3, ?-catenin, and CBP. ICG-001 inhibited ?-SMA expression/transcription in response to TGF-? as well as ?-SMA promoter occupancy by ?-catenin and CBP, demonstrating a previously unknown requisite TGF-?1/?-catenin/CBP-mediated pro-EMT signaling pathway. Clinical relevance was shown by ?-catenin/Smad3 co-localization and CBP expression in AEC of IPF patients. These findings suggest a new therapeutic approach to pulmonary fibrosis by specifically uncoupling CBP/catenin-dependent signaling downstream of TGF-?.

SUBMITTER: Zhou B 

PROVIDER: S-EPMC3293544 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Interactions between β-catenin and transforming growth factor-β signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP).

Zhou Beiyun B   Liu Yixin Y   Kahn Michael M   Ann David K DK   Han Arum A   Wang Hongjun H   Nguyen Cu C   Flodby Per P   Zhong Qian Q   Krishnaveni Manda S MS   Liebler Janice M JM   Minoo Parviz P   Crandall Edward D ED   Borok Zea Z  

The Journal of biological chemistry 20120112 10

Interactions between transforming growth factor-β (TGF-β) and Wnt are crucial to many biological processes, although specific targets, rationale for divergent outcomes (differentiation versus block of epithelial proliferation versus epithelial-mesenchymal transition (EMT)) and precise mechanisms in many cases remain unknown. We investigated β-catenin-dependent and transforming growth factor-β1 (TGF-β1) interactions in pulmonary alveolar epithelial cells (AEC) in the context of EMT and pulmonary  ...[more]

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